Process for preparing 3-methylflavone-8-carboxylic acid



United States Patent Ofifice The present invention relates to a new and advantageous process for the preparation of 3-methyl-fiavone- 8-carb0xylic acid, a very important intermediate for obmacological properties.

This acid has heretofore been prepared from the intermediate 3-propionyl-2 such procedure is relatively more complicated and less According to this invention, an 8-alkenyl-3-methylfiavone, for example the 8-propenylor 8-allyl derivative, not described in literature, ther on, in Examples 1 and 2, is submitted to the action of an oxidizing agent, such as for example KMnO in the presence of magnesium salts, in pyridine/water medium, in order to transform it in 3-methylfiavone-8- carboxylic acid, which is i lon. o

EXAMPLES (1) 8-allyl-3-methyl-flavone In a round-bottomed, three-necked, 1 liter flask, fitted with stirrer, reflux bulb cooler, with CaCl closure and an open neck, for a wide-mouthed funnel for powders, 100 g. of 3-allyl-2-hydr0xypropiophenone (described by T. Takahoschi et al., J. Pharm. Soc. Japan 74, 48 (1954) and abstracted in CA. 49, 1623), are mixed under stir- 3,350,411 Patented Oct. 31, 1967 ring with 220 g. of benzoyl chloride. To this mixture are then added, slowly and under agitation, 250 g. of sodium benzoate powder.

The mixture is heated on an oil bath at 185-195 C. for 8 hours, then while still melted, is poured in a dish. It is allowed to cool, taken up with about 700 ml. comwater; about 700 g. of ice are added and to this mixture, kept under agitation, the former dropwise.

ligroine in the ratio 1:5, giving 106 g. of yellow crystalline product, M.P. 8789 C.

(3) 3-methylflav0ne-8-carb0xylic acid 30 g. of 8-allyl-3-methylflavone are suspended in a mixture of 165 ml. water and 110 ml. pyridine, in a largenecked 2 1. container, provided with agitator and thermometer, placed in a cold water circulation bath.

In a period of two hours a mixture of 92 g. of potassium permanganate and 27.9 g. of magnesium nitrate hexahydrate is added in portions.

The temperature is maintained within 15 and 18 C. When the addition is a Biichner funnel, ml. of water in which it dissolves by vigorous stirring and addition of NaHCO The solution is filtered, if necessary, and the filtrate is poured, under vigorous stirring, into a mixture of 200 ml. HCl and 200 ml. water. The separated solid is filtered, washed to neutral with water and dried in an oven at 70 C., in vacuum, giving 12-125 g. of 3-methylflavone-8-carboxylic acid, M.P. 215-20 C., with an acidimetric titer of 97.5%, sufficiently pure for the successive use.

By crystallization from ml. of methanol, 9.1 g. of crystalline product, M.P. 227-229 C., are obtained.

Analysis for C H O Calculated: C, 72.85%; H, 4.31%. Found: C, 72.81%; H, 4.28%.

(4) 3-methylflavone-8-carb0vcylic acid By the above procedure and employing the following ratios of the reactants:

30 g. 8-propenyl-3-methylfiavone 150 ml. pyridine 200 ml. water 45.9 g. KMnO 3 (5) piperidinethyl-3-met'hylflavone 8 carboxylatefl Cl 7 .29 g. of the crystalline 3-methylfiavone-8-carboxylic acid, obtained in Examples 3 and 4, and 4.79 g. of pipcridinoethyl chloride hydrochloride (equimolar amounts) are suspended in 100 ml. of isopropanol, distilled on C210, and added, under stirring, to 24.9 ml. of 2.09 N methyl alcoholic KOH.

The mixture is stirred and boiled for 30 minutes, immediately cooled, and, finally evaporated under reduced pressure. The residue is taken up with benzene, the salts are dissolved by adding water alcalinized with a little of Na CO and the mixture is transferred in a separatory funnel. It is shaked, the organic phase is separated, washed once with water, dried on Na SO and evaporated under reduced pressure.

The residual base, extracted with ether, gives the hydrochloride by treatment with chlorhydric ethanol. On crystallization from methanol, piperidinoethyl-3-methylflavone-8-carboxylate hydrochloride, M.P. 232-34 C., is obtained.

Analysis for C I-I O NCL Calculated: N, 3.27%; Cl, 8.14%. Found: N, 3.16%; Cl, 8.20%.

(6) morpholinoethyl-3-melhylflav0ne-8-carb0xylate.HCl

On reacting equimolar amounts of 3-methylflavone-8- carboxylic acid and morpholinoethyl chloride hydrochloride, according to the process described in the above example the morpholinoethyl-3-methylflavone-8-carboxylate.HCl is obtained.

C H O NCl, M.P. 233-34 C.

In analogous manner the following products are obtained:

8 carboxylate.

4 Diethylaminopropyl 3 methylfiavone 8 carboxylate.I-ICl, C H O NCl, M.P. 18789 C.

(1) This product, not described in literature, is obtained by isomerization of the corresponding 3-allylderivative according to the usual procedure described in Organic Reactions, 2, 27 (1944), as a yellow solid (from methanol), M.P. 84-86 C.

What I claim is:

1. A process for preparing 3-methylfiavone-8-carboxylic acid having the following formula:

/(JICH3 comprising oxidizing an 8-alkenyl-3-rnethylfiavone with an oxidizing agent capable of oxidizing a double bond in the side chain in the presence of magnesium nitrate in a pyridine/water medium at a temperature of 15 18 C.,

filtering the reaction products, acidifying the filtrate with mineral acid and recovering the separated solid 3-methylfiavone-8-carboxylic acid product.

2. A process in accordance with claim 1, characterized in that the product subjected to oxidation is 8-allyl-3- methylflavone.

3. A process in accordance with claim 1, characterized in that the product subjected to oxidation is 8-propenyl- 3-methylfiavone.

4. A process in accordance to claim 1 wherein the product subjected to oxidation is selected from the group consisting of:

8-allyl-3-methylfiavone and 8-propenyl-3-methylflavone and the oxidizing agent is potassium permanganate.

References Cited UNITED STATES PATENTS 3,244,706 4/1966 Sutton 260-2472 

1. A PROCESS FOR PREPARING 3-METHYLFLAVONE-8-CARBOXYLIC ACID HAVING THE FOLLOWING FORMULA: 